Veterinary nurses are often asked about skin conditions and it is important to understand that canine atopic dermatitis can resemble many other pruritic skin diseases and to be aware of the many skin issues that can occur when carrying out consultations, conducting telephone triages and booking consultations, as first opinion practices are inundated with itchy dog phone calls. Hill et al (2006) state that pruritic skin disease accounts for just under half of dermatological problems in first opinion practice. Canine atopic dermatitis can very easily be misdiagnosed for other skin issues or diseases which resemble canine atopic dermatitis.
Canine atopic dermatitis is a common and complex allergic skin disease that affects canines all over the world. It is defined by the American College of Veterinary Dermatology as ‘a genetically predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features associated with IgE antibodies most commonly directed against environmental allergens’ (Olivry et al, 2001; Bizikova et al, 2015a; Santoro et al, 2015). This is the ‘inside-outside’ theory. The ‘inside-outside’ theory proposes that a loss of skin barrier function allows allergens and microbes to easily penetrate through the epidermis, which increases allergen exposure to epidermal immune cells (Santoro et al, 2015).
Environmental allergies and canine atopic dermatitis often develop between the age of 6 months and 3 years (Griffin and DeBoer, 2001; Saridomichelakis and Olivry, 2016). Atopic dermatitis can be seen globally, as a report from Hill indicated that pruritic skin disease accounted for 30–40% of dermatological problems in first opinion practice (Hill et al, 2006; Paterson, 2019). Owners will often report behaviour such as impulsive scratching, rubbing, chewing, licking, excessive grooming, scooting and head shaking. These behaviours can be frustrating for both the patient and the owner.
In the veterinary clinic, patients will present with clinical signs such as pruritus, self-induced alopecia, self mutilation and inflammation of the ventral abdomen, distal limbs, paws, axilla and inner pinnae. The periocular, perioral and perianal regions are the most common sites of erythema. Erythema is described as the reddening of the skin because of inflammation (Garland, 2013). Sequelae often arise such as pustules and crusts, which can lead to secondary infections and further complications (Griffin and DeBoer, 2001; Favrot, 2009). Itching and lesions of the external ear flap are present in half of atopic dermatitis cases (Favrot, 2009).
The scrutiny on past studies in this field led to the inception of the task force on canine atopic dermatitis in 1999 by the American College of Veterinary Dermatology. The research carried out by the American College of Veterinary Dermatology task force in the past decade, among other findings which have had similar results, has resulted in the review and adoption of clear and concise terminology, definitions, clinical signs, diagnosis and treatment so patients may be treated appropriately and accurately (Olivry et al, 2001; Bizikova et al, 2015a; Chermprapai et al, 2018; Prelaud and Laprais, 2020).
Diagnosis
Canine atopic dermatitis is diagnosed initially with the clinical evaluation of a combination of criteria that are closely associated with the disease (DeBoer and Hillier, 2001). Once it is certain that the patient meets the criteria and other differential diseases are ruled out (Table 1), skin tests are conducted. Several schemes have been suggested in order to determine the uniform clinical criteria for the diagnosis of canine atopic dermatitis, but none of these systems are perfect (Table 2). There are many factors that can make accurately diagnosing canine atopic dermatitis difficult. Numerous common pruritic skin diseases exist that may be mistaken for canine atopic dermatitis and the patient may be diagnosed with one of them without correctly investigating them (DeBoer and Hillier, 2001; Hensel et al, 2015).
Clinical signs of canine atopic dermatitis.
Pruritic skin diseases.
| Ectoparasitic skin diseases |
|
| Microbial skin infections |
|
| Allergic skin diseases |
|
| Neoplastic disease |
|
Favrot's criteria.
| Favrot's criteria* for canine atopic dermatitis (Favrot et al, 2010) |
| Atopic dermatitis is very likely if ≥5 of the following criteria are present and other differentials have been ruled out: |
| Affected ear pinnae (but not pinnal margins) |
| Affected front feet |
| Age of onset <3 years |
| Chronic or recurrent yeast infections |
| Corticosteroid-responsive pruritus |
| Mostly indoor lifestyle |
| Non-affected dorsolumbar area |
| Pruritus without skin lesions at onset |
At least 5 positives = 85% sensitivity (miss 15%); 79% specificity (falsely diagnose 21%)
In order to obtain a definitive diagnosis and rule out other skin diseases that resemble canine atopic dermatitis, veterinarians and veterinary dermatologists teamed up to form the International Committee on Allergic Diseases of Animals. They continued on from the research committee task force American College of Veterinary Dermatology and developed practical guidelines to help veterinarians diagnose canine atopic dermatitis. The International Committee on Allergic Diseases of Animals filtered through a total of 81 relevant publications and a combination of expert opinion and relevant papers brought the team to the conclusion that three main areas should be focused on when diagnosing canine atopic dermatitis (Hensel et al, 2015):
Ruling out flea atopic dermatitis. Figure shows the distribution of flea atopic dermatitis lesions and pruritus.
Lice/Cheyletiella. Lice: No visible lesions, or mild scaling and excoriation. Cheyletiella: Marked dorsal seborrhea.
Distribution of skin lesions and pruritus associated with sarcoptic mange. Lesions include papular eruption, erythema, scaling, excoriations.
Distribution of skin lesions and pruritus associated with trombiculiasis. Lesions usually manifest as eruption.
Distribution of skin lesions and pruritus associated with otoacariasis. Lesions include erythema, dark-brown, coffee ground-like discharge.
Distribution of skin lesions and pruritus associated with demodicosis. Lesions include focal, multi-focal or generalised alopecia, scaling, erythema, follicular casts, comedones, furunculosis.
Allergy testing should only be considered if there is strong clinical evidence of allergy and after all other possible diagnoses have been ruled out.
The American College of Veterinary Dermatology task force has developed useful measuring tools to help determine extent and stage of the disease and to help clinical trials determine whether an assigned treatment is effective. These measuring tools are known as CADESI-3, CADESI-4 and CADLI. They are useful tools in helping practitioners diagnose canine atopic dermatitis and monitor therapeutic interventions.
A fourth version, the lesion severity scale CADESI-4 was designed for trials lasting no more than 6 weeks. It is a much simpler version compared to the other scales. CADE-SI-4 comprises of 20 body sites typically affected in atopic dogs (Figure 8). Three lesions (erythema, lichenification and alopecia/excoriation) were scored from 0 to 3 at each site. The CADESI-4 had satisfactory validity, reliability and sensitivity to change. On average, the time to administer a CADESI-4 was one-third that of a CADESI-3. Proposed benchmarks for mild, moderate and severe atopic dermatitis skin lesions are 10, 35 and 60, respectively (Olivry et al, 2014).
Common body regions evaluated in CADESI-4.
International Committee on Allergic Diseases of Animals members voted to use 3 lesions from the CADESI-3 design as they are highly relative to the diseases: erythema is a sign of acute inflammation; lichenification is a sign of chronic canine atopic dermatitis and the combination of excoriation and alopecia as markers of pruritus (Olivry et al, 2014). Body site selection was taken from a prospective study on the clinical features of chronic canine atopic dermatitis and its diagnosis. These body regions are ranked as follows by decreasing sensitivity and specificity: (i) hind feet; (ii) ear pinnae; (iii) forefeet; (iv) axillae; (v) lips; (vi) flexural areas; (vii) genitalia or ventral tail; (viii) lateral thorax or flanks; (ix) elbows; (x) hindlimbs; and (xi) abdomen and/or inguinal areas (Favrot et al, 2010; Olivry et al, 2014).
It is also very important for owners to monitor their dog's behaviour and score criteria the veterinarian cannot monitor, such as pruritus severity at home. The pruritus visual analog scale (Figure 9) (Olivry et al, 2007) can assist with this and further help practitioners diagnose and monitor therapeutic development.
Pruritus visual analog scale.
Another practical tool practitioners can use to grade canine atopic dermatitis lesions, which requires scoring only the frequently affected body regions, is the CADLI (Figure 10). The CADLI was found to be an effective measure of canine atopic dermatitis lesion severity, strongly correlating with CADESI-03. The convenience of CADLI makes it suitable for use in both clinical research and practice.
CADLI lesion score tool.
To effectively diagnose canine atopic dermatitis, veterinarians can combine the lesion scale indexes shown along with ruling out other pruritic skin diseases which have similar clinical signs, using complete evaluation and interpretation of clinical signs and history, and allergy testing.
Epithelial structure
It can be easy to forget and overlook that the skin has many very important functions and is the largest organ of the body. The skin, like all other organs, is complex in structure, suffers from wear and tear and is affected by diseases (Lloyd and Patel, 2012; Garland, 2013; Safari Veterinary Care Centers, 2021). The skin is composed of three major layers. The epidermis is the outermost layer which is composed of four layers as seen in Figure 11. These layers are from outermost to inner: the horny layer, the granular layer, the spinous layer and the basal layer. Beneath the epidermis is the dermis, and the inner most layer is the subcutaneous tissue (Garland, 2013).
The epidermal composition shows the cellular structure of the 4 epidermis layers. 1. Horny layer (Superficial) 2. Granular layer 3. Spinous layer 4. Basal layer (Garland, 2013).
The epidermis is the tough, waterproof outer layer, made of keratinised stratified squamous epithelium that is continuously being worn away. The epidermis is the superficial layer and so is exposed to a wide variety of stressors, be they chemical, physical or biological. It is the horny layer that becomes affected by canine atopic dermatitis. The horny layer, or stratum corneum, is the epidermis' physical barrier and consists of anuclear flattened polyhedral corneocytes and keratinocytes which are embedded in lipid matrix (Garland, 2013; Chermprapai et al, 2018). It is the integrity of these lipids, composed of free fatty acid, cholesterol and ceramides, which are most important in maintaining the skin barrier function (Garland, 2013; Chermprapai et al, 2018).
The dermis is the thicker underlying layer that contains the nerves, blood vessels and hair roots. It is made of areolar connective tissue containing collagen and elastic fibres (Garland, 2013). Table 3 shows structural defects in the skin that predispose or result in disease.
Structural defects that predispose or result in disease, as shown in the table below it is the defect in the uppermost layer/epidermis that causes dermatitis.
| Skin | Layer | Structural components | Disease |
|---|---|---|---|
| Epidermis | Horny | Intercellular lipid (ceramides) | Atopic dermatitis |
| Intercellular lipids, cornified envelope and keratin or desmosomal components | Non-epidermolytic and epidermolytic ichthyosis | ||
| Granular and spinous | Intercellular proteins including desmoglein 1 and desmocollin | Pemphigus foliaceus and pemphigus erythematosus | |
| Basal | Desmoglein 3 | Pemphigus vulgaris | |
| All | Loss of epidermal cohesion due to weak desmosomal attachments | Canine Darier's disease | |
| Dermoepidermal junction | Basal | Collage VXII (bullous pemphigoid antigen) | Bullous pemphigoid |
| Basement membrane zone | Laminin 332 (laminin 5) and other proteins | Mucous membrane pemphigoid | |
| Junctional epidermolysis bullosa | |||
| Collagen VII | Acquired and dystrophic epidermolysis bullosa | ||
| Dermis | Collagen | Defects in collagen synthesis and bundle formation | Ehlers-Danlos syndrome |
Atopic dermatitis causes
Canine atopic dermatitis is multifaceted and has a highly complex pathogenesis (Santoro et al, 2015). Hypersensitivities, genetic predisposition and an abnormal immune response, along with skin barrier defects, are all possible factors causing canine atopic dermatitis (Gedon and Mueller, 2018).
Genetics and breed predisposition
Early studies by the American College of Veterinary Dermatology task force found that no significant difference could be found in total IgE levels and DLA haplotype between healthy and atopic dogs. However, the combination of the haplotypes DLA-A3 and R15 was found to be present more frequently in atopic versus healthy dogs (Bizikova et al, 2015b).
Skin barrier defect
As mentioned previously, the stratum corneum is the outer-most layer of the epidermis and it plays a key part in cutaneous barrier function. Any defects can lead to an increase in epidermal water loss and allow environmental agents to penetrate into the skin (Gedon and Mueller, 2018; Combarros et al, 2020). The skin barrier may become defected as a result of decreased filaggrin concentrations (Gedon and Mueller, 2018) (Figure 12). This concentration loss is due to the transcriptional effect of Th2 type cytokines (Combarros et al, 2020). Caspase 14 metabolises filaggrin into moisturising molecules, such as free amino acids and peptides. These reduced concentrations influence the skin barrier function and hydration of the stratum corneum.
Filaggrin (FLG) breakdown by Caspase 14.
Conflicting results regarding filaggrin metabolism in atopic dogs have been published with lower and higher caspase 14 concentrations (Combarros et al, 2020). Alterations in the ceramide composition of lesional canine atopic skin have been described, contributing to disorganisation of the lipid envelope leading to defects in the epidermal barrier (Gedon and Mueller, 2018; Combarros et al, 2020).
Environmental allergies and increased IgE antibodies
There are numerous allergens or antigens from the environment that cause canine atopic dermatitis. These include what should be harmless particles and microscopic parasites such as dust mites, house dust, grass, weed and tree pollen, and insect antigens (Hill and DeBoer, 2001). Canine atopic dermatitis is multifaceted with one of its factors being an IgE-mediated hypersensitivity response to environmental allergens. However, it is argued that allergen-specific IgE may be detected in dogs that do not have clinical manifestations of atopic dermatitis and that measurement of IgE does not help to discriminate between dogs that will later develop disease and dogs that will not (Marsella et al, 2012).
Furthermore, measurement of IgE is not of use in discriminating between atopic dogs, healthy dogs and dogs with parasitic diseases. It is suggested that not all IgE is pathogenic (Marsella et al, 2012). Altogether, these considerations highlight the fact that the initial view of atopic dermatitis as solely an IgE-mediated allergic disease does not completely explain the pathogenesis of this complex disease and that new definitions and approaches are needed (Pucheu-Haston et al, 2015; Marsella and De Benedetto, 2017). When allergens penetrate the epidermis it causes a chain reaction and communication between dendritic cells, T helper cells, cytokines, IgE antibodies and the nervous system. Interleukin-31 is known to be one of the key mediators that cause itch, along with cytokines IL-2 and IL-6 (Brandt and Sivaprasad, 2011).
Diet
Cutaneous adverse food reactions and atopic dermatitis in dogs are often indistinguishable from each other on historical and clinical grounds alone (Hillier and Griffin, 2001). Around 40% of dogs suffering from atopic dermatitis have sensitisation to food allergens. The most common clinical manifestation from food allergy is pruritic dermatitis (Saridomichelakis and Olivry, 2016). This is known as food-induced atopic dermatitis (Koch, 2015). Adverse food reactions are often correlated with atopic dermatitis in the dog. Ingestion of food and environmental allergens may trigger exacerbations of atopic dermatitis (Pucheu-Haston et al, 2015).
Food allergy is a response to amino acids or proteins of particular food sources, most commonly beef, chicken, pork or turkey. The most common clinical signs of food-induced atopic dermatitis are pruritus, inflammation, gastrointestinal tract disorders and respiratory issues (Danforth Animal Hospital, 2021). There are no therapeutic drugs that will be effective towards resolving food-induced dermatitis. The best treatment is to find out what the offending food triggers are via IgE allergy testing along with a food trial of an anallergenic/hypoallergenic diet. It may take up to 8 weeks for offending food products to leave the system, therefore it is important for the food trial to continue for 8–12 weeks (Danforth Animal Hospital, 2021).
Atopic dermatitis management
Canine atopic dermatitis is multifaceted and a multi-modal approach may be needed to manage the disease. Many factors may need to be taken into consideration, such as stage of the disease, and whether the flare up is acute or chronic. Food flare ups and flea allergy dermatitis need ruling out along with other skin conditions that may be mistaken for canine atopic dermatitis.
Veterinarians should weigh up the severity of each patient's canine atopic dermatitis clinical signs and the likely compliance of owners. A combination of allergen avoidance, allergen specific immunotherapy and symptomatic treatment with effective drugs which have proven efficacy may be effective (Saridomichelakis and Olivry, 2016). Drugs include symptomatic therapeutics such as glucocorticoids, which inhibit inflammatory processes and molecules such as cytokines, chemokines, arachidonic acid metabolites and adhesion molecules (van der Velden, 1998). Ciclosporin, which suppresses the immune system, and oclacitinib (Apoquel), which inhibits Janus kinase, blocking the itch signal to the brain (Saridomichelakis and Olivry, 2016). The newest canine atopic dermatitis drug on the market is lokivetmab (Cytopoint), an injectable anti-canine-IL-31 monoclonal antibody to treat clinical manifestations of atopic dermatitis in dogs (Moyaert et al, 2017).
Generally, it is recommended that acute flares should be managed with weekly bathing with mild shampoos, oral and topical glucocorticoids or oclacitinib. For chronic atopic dermatitis, offending allergens need to be identified and avoided. Frequent bathing and upkeep of skin and coat care is vital. The most effective medications in reducing chronic lesions and pruritus include lokivetmab, oral and topical steroids, oclacitinib, ciclosporin, intermittent topical glucocorticoid application and allergen specific immunotherapy are recommended treatments (Little et al, 2015).
Conclusions
Veterinary nurses carrying out nurse consultations are often asked by pet owners about skin issues, therefore, it is important to have a good understanding of canine atopic dermatitis along with the plethora of other skin issues dogs suffer from. The development and severity of canine atopic dermatitis is multifaceted and the pathogenesis is complicated involving genetic, immunological, environmental, pharmacological, and physiological factors, along with the functionality of the skin barrier.
It is now well-documented that the majority of cases will be different in terms of breed, stage and causes and so a multimodal approach of the wide variety of therapeutics available should be considered.